Topical skin lightening additive and composition with amino acids and nicotinamide compounds

ABSTRACT

Skin lightening additives and personal care compositions containing amino acids and nicotinamide compounds. The compositions are useful for attaining even skin color and reducing pigmentation, age spots and discoloration.

FIELD OF THE INVENTION

The present invention is directed to a skin lightening additive andtopical compositions comprising the additive.

BACKGROUND OF THE INVENTION

Many consumers are concerned with the characteristics of their skin. Forexample, consumers are concerned with the degree of pigmentation oftheir skin, freckles and/or age spots. Other consumers wish to reduceskin darkening caused by exposure to sunlight. To meet the needs ofconsumers, many attempts have been made to develop products that improveskin characteristics. The products developed thus far, however, oftentend to have low efficacy, undesirable side effects or both. There is anincreasing interest to develop a cosmetic composition that comprises newskin lightening additives.

Glutathione (GSH) is a tripeptide that consists of glutamate, cysteine,and glycine. It is present in all mammalian tissues. It is the mainanti-oxidant in the living body: it protects cells from oxidation byquenching reactive oxygen species. Increased cellular levels of GSHprotect cells against oxidative damage, toxic compounds, and radiation(Meister, J. Biol. Chem. 263: 205-217, 1988; Meister, Science200:471-477, 1985). While true in all areas of the body, this isparticularly important in the skin, which is so greatly exposed to thedamaging effects of radiation, particularly UV radiation, andenvironmental pollutants. Decrease in the intracellular concentration ofglutathione in skin is associated with cell damage, inflammation, skindarkening, discoloration, spots or freckles caused by exposure toultraviolet radiation, physiological aging, and the like.

A logical approach to achieve skin lightening and/or to fight skindarkening, discoloration or pigmentation would seem to be to providecells with an exogenous source of GSH (e.g. through ingestion or topicaldelivery). Indeed, GSH has been sometimes marketed as a skin lighteningingredient. Unfortunately, GSH is not bioavailable when administeredexogenously, i.e. where localized extracellularly, GSH is broken downinto its constituent amino acids (glutamate, cysteine, and glycine) forcellular uptake and synthesis of the GSH tripeptide. Thus, GSH is notdirectly transported into the cells and therefore does not itself resultin an intracellular increase of GSH or any benefits associatedtherewith. Cysteine, one of the amino acids in GSH, may increasecellular levels of GSH, but exposed sulfhydryl group of cysteine rendersit unstable and reactive and also causes strong unpleasant odor. Unlikecysteine, cystine can be administered safely; cystine is transportedinto the cell and converted to cysteine within the cell, the cysteinethen being available for intracellular GSH production.

Topical compositions containing various amino acids and other skin careactives have been described, see e.g. Tanojo U.S. Pat. No. 7,300,649,Laboratoire Filorga product, Schlachter WO 00/03689, Ermolin et al.US2011183040, Garlen et al. U.S. Pat. No. 4,707,354, Muller et al. U.S.Pat. No. 8,361,446, Hermann et al. U.S. Pat. No. 8,241,681. Compositionsfor potentiating intracellular glutathione production have beendescribed. See e.g. Chiba et al. U.S. Pat. No. 7,740,831, Crum et al(U.S. RE37934, U.S. RE42645, WO2016/033183, and US20050271726); MammoneU.S. Pat. No. 6,149,925, and Perricone US 20060063718.

Cystine is normally derived from the diet. Delivery of cystine fromtopical compositions, however, is challenging due to its extremely lowsolubility in biologically acceptable vehicle in a neutral pH range,which is the pH range required for topical application. The solubilityof cystine in water is 0.112 mg/ml at 25° C.; cystine is more soluble inaqueous solutions with pH less than 2 or pH above 8.

The present invention is based in part on a surprising finding that acombination of modified GSH block amino acid mix, comprising cystine,glutamate and glycine, with a member of a group of nicotinamide-derivedcompounds achieves a synergistic increase in skin lightening, thuscounter-acting the drawback of cystine's low solubility.

SUMMARY OF THE INVENTION

In one embodiment, a personal care composition according to theinvention comprises:

a. a skin lightening additive comprising by weight of the composition:

-   -   i. from about 0.001 to about 2% of cystine;    -   ii. from about 0.01 to about 10% of a glutamate source selected        from the group consisting of glutamine, glutamic acid,        pyroglutamic acid, and mixtures thereof;    -   iii. from about 0.01 to about 10% of glycine;    -   iv. and from about 0.05 to about 10% of a nicotinamide compound;        and

b. a cosmetically acceptable carrier;

c. wherein the pH of the composition is in the range of from about 3.5to about 8.5.

In one embodiment, the topical cosmetic skin composition is a leave-oncomposition, especially a leave-on non-solid composition.

In one embodiment, the present invention provides a method of improvingskin appearance, comprising applying the topical cosmetic skincomposition to the skin.

In one embodiment, the present invention provides a method of improvingskin appearance, comprising applying the personal care composition tothe skin.

In one embodiment, the present invention provides a method of attainingeven skin color and reducing pigmentation, age spots and discoloration,comprising applying the composition to skin.

The compositions of the invention improve skin appearance due tochronological aging or photoaging through even skin tone, skinlightening, counter-acting discoloration, pigmentation, age spots, andskin darkening, resulting from exposure to UV light/sunlight, orenvironmental pollutants. A preferred method of obtaining the benefitsof the composition is via regular/chronic topical application of thecomposition, to prevent development of skin damage which may result fromeven routine exposure to UV light.

DETAILED DESCRIPTION OF THE INVENTION

Throughout the specification and claims, the following terms take themeanings explicitly associated herein, unless the context clearlydictates otherwise. The phrases “in one embodiment” and “in someembodiments” as used herein do not necessarily refer to the sameembodiment(s), though it may. Furthermore, the phrases “in anotherembodiment” and “in some other embodiments” as used herein do notnecessarily refer to a different embodiment, although it may. Thus, asdescribed below, various embodiments of the invention may be readilycombined, without departing from the scope or spirit of the invention.In addition, each of the examples given in connection with the variousembodiments of the invention which are intended to be illustrative, andnot restrictive.

Except in the examples, or where otherwise explicitly indicated, allnumbers in this description indicating amounts of material or conditionsof reaction, physical properties of materials and/or use are to beunderstood as modified by the word “about.” All amounts are by weight ofthe final composition, unless otherwise specified. The disclosure of theinvention as found herein is to be considered to cover all embodimentsas found in the claims as being multiply dependent upon each otherirrespective of the fact that claims may be found without multipledependency or redundancy. In specifying any range of concentration oramount, any particular upper concentration can be associated with anyparticular lower concentration or amount.

“Comprising” is intended to mean “including” but not necessarily“consisting of” or “composed of.” In other words, the listed steps oroptions need not be exhaustive.

“Skin” is meant to include skin on the face, neck, chest, back, arms(including underarms), hands, legs, buttocks and scalp.

“Leave-on composition” refers to a composition that is applied to theskin and is not intended to be washed or rinsed off for some period oftime, specifically hours, as contrasted with skin cleansing or wash-offor rinse-off compositions which are rinsed off or washed off immediatelyor minutes after the application.

“Non-solid” with respect to the composition means that the compositionhas a measurable viscosity (measurable for instance with a BrookfieldViscometer DV-I+(20 RPM, RV6, 30 Seconds, 20° C.) in the range of from 1Pas to 500 Pas, preferably from 2 Pas to 100 Pas, more preferably from 3Pas to 50 Pas.

“Personal care composition” refers to any product applied to a humanbody for improving appearance, sun protection, cleansing, odor control,moisturization or general aesthetics. Non-limiting examples of personalcare compositions include skin lotions, creams, gels, lotions, facialmasks, sticks, shampoos, conditioners, shower gels, toilet bars,antiperspirants, deodorants, shave creams, depilatories, lipsticks,foundations, mascara, sunless tanners and sunscreen lotions.

“Skin cosmetic composition” refers to any product applied to a humanbody for improving appearance, sun protection, reducing wrinkledappearance or other signs of photoaging, odor control, skin lightening,even skin tone, or general aesthetics. Non-limiting examples of topicalcosmetic skin compositions include skin lotions, creams, facial masks,gels, sticks, antiperspirants, deodorants, lipsticks, foundations,mascara, liquid or gel body washes, soap bars, sunless tanners andsunscreen lotions.

Personal care composition of the present technology is preferably aleave-on non-solid skin cosmetic composition, because such compositionsare the most challenging in terms of incorporating cystine due to itslow solubility.

Modified Glutathione (“GSH”) Amino Acids

The GSH amino acid mix according to the present invention comprisesamino acids (glutamate, cystine and, and glycine) and nicotinamidecompounds.

Amino acids included in the inventive composition are present as Lstereo isomers, since this is the most abundant and natural isomericform found in nature. Since the building blocks of naturally-occurringproteins found in human skin, hair and nails are amino acids with the Lisomeric form, it is expected that L stereo isomer amino acids containedwithin personal care products of the present invention can have agreater interaction with these proteins that is intrinsically morebiocompatible in nature compared to the D stereo isomeric form. Inaddition, commercial production and supply of L stereo isomer aminoacids is significantly higher compared to the D stereo isomeric form.Finally, L stereo isomer amino acids are also more cost effective toproduce, more sustainable, more eco-friendly and available at a lowercost compared to D stereo isomer amino acids.

Any of the amino acids included in the present invention may be in theform of a salt, ester, or a salt thereof and the term “cystine,”“glutamate source”, and “glycine” used in the present specification alsoencompasses salts, esters, and salts of such esters. The salt, ester,and salt of such ester is not particularly limited as long as it isacceptable for topical application. For example, salts with inorganicacid or organic acid or anionic surfactants can be mentioned. As theinorganic acid, for example, hydrochloric acid, hydrobromic acid, nitricacid, sulfuric acid, phosphoric acid and the like can be mentioned, andas the organic acid C1-C18 linear, branched or cyclic, saturated orunsaturated, unsubstituted or substituted with heteroatoms, for exampleformic acid, acetic acid, trifluoroacetic acid, propionic acid, lacticacid, tartaric acid, oxalic acid, fumaric acid, succinic acid, maleicacid, citric acid, malonic acid, methanesulfonic acid, stearic acid,oleic acid, 12-hydroxystearic acid, ricinoleic acid, and the like can bementioned.

As the salt with a base, for example, alkali metal salts such as sodiumsalt, potassium salt and the like, alkaline earth metal salts such ascalcium salt, magnesium salt and the like, and the like can bementioned.

Esters of amino acids are typically C₁-C₈ esters or salts thereof, or inthe alternative C₁-C₅ esters, or in the alternative C₁-C₃ esters. Suchesters may be straight or branched or cyclic. Especially esters ofcystine are beneficial, due to their increased solubility, compared tocystine. Methyl and ethyl esters of cystine or salts thereof are mostpreferred, due to their efficacy to boost glutathione production andprovide antioxidant activity. When salts of esters are used, the samesalts are suitable as listed above.

Glutamate source can be present in the form of its functionalequivalents—glutamine, glutamic acid and/or pyroglutamic acid and/ortheir esters or salts may be employed. Pyroglutamic acid (and/or saltsthereof) is preferred since it is more stable than glutamine or glutamicacid. In one embodiment, the skin lightening additive includes cystineand pyroglutamic acid and glycine (and/or salts thereof).

Nicotinamide Compounds

Nicotinamide compounds suitable to be included in the present inventionselected from the group consisting of Formula I, Formula II, FormulaIII, and mixtures thereof:

-   -   wherein    -   R is —CONH₂ or —CH₂OH or —COOR₂;    -   R₁ is C1 to C5 straight or branched alkyl group or a furanosyl        group or a deoxyfuranosyl group or a pyranosyl group or a        deoxypyranosyl group;    -   R₂ is C1-C24 straight or branched alkyl or alkenyl group.

Exemplary derivatives of the foregoing compounds include nicotinic acidesters, including non-vasodilating esters of nicotinic acid, nicotinylamino acids, nicotinyl alcohol esters of carboxylic acids, nicotinicacid N-oxide and niacinamide N-oxide. As used herein, “non-vasodilating”means that the ester does not commonly yield a visible flushing responseafter application to the skin in the subject compositions (the majorityof the general population would not experience a visible flushingresponse, although such compounds may cause vasodilation not visible tothe naked eye, i.e., the ester is non-rubefacient). Non-vasodilatingesters of nicotinic acid include tocopherol nicotinate, myristylnicotinamide, and inositol hexanicotinate.

Other derivatives of nicotinamide resulting from substitution of one ormore of the amide group hydrogen. Examples of derivatives ofnicotinamide useful herein include nicotinyl amino acids, derived, forexample, from the reaction of an activated nicotinic acid compound(e.g., nicotinic acid azide or nicotinyl chloride) with an amino acid,and nicotinyl alcohol esters of organic carboxylic acids (e.g., C1-C18).Specific examples of such derivatives include nicotinuric acid(C8H8N2O3) and nicotinyl hydroxamic acid (C6H6N2O2). Exemplary nicotinylalcohol esters include nicotinyl alcohol esters of the carboxylic acidssalicylic acid, acetic acid, glycolic acid, and palmitic acid, myristicacid, linoleic acid, oleic acid and the like. Other examples ofnicotinamide compounds useful herein are 2-chloronicotinamide,6-methylnicotinamide, N-methyl-nicotinamide, and niaprazine. Vitamin B3compounds are well known in the art and are commercially available froma number of sources, e.g., the Sigma Chemical Company (St. Louis, Mo.);ICN Biomedicals, Inc. (Irvin, Calif.) and Aldrich Chemical Company(Milwaukee, Wis.). One or more vitamin B3 compounds may be used herein.

In one embodiment nicotinamide compounds include nicotinamide, N-methylnicotinamide, iso-nicotinamide, nicotinamide riboside and mixturesthereof. Nicotinamide compounds used in the present invention may becapable of forming salts, complexes, hydrates and solvates. Suitablesalts are selected from fluoride, chloride, bromide, iodide, formate,acetate, fatty acid carboxylate, fatty acid dicarboxylate, oxalate,ascorbate, benzoate, carbonate, citrate, carbamate, gluconate, lactate,methyl bromide, methyl sulfate, nitrate, phosphate, diphosphate,succinate, sulfate, trifluoroacetate or trifluoromethanesulfonate.Nicotinamide furanosides of the present invention (i.e. nicotinamideriboside) comprise derivatives where the furanosyl group is derived fromribose (i.e. ribofuranos-1-yl) or arabinose and the deoxyfuranosyl groupis derived from deoxyribose. Nicotinamide pyranosides comprisederivatives where the pyranosyl group is derived from ribose, arabinose,xylose, lyxose, allose, altrose, glucose, mannose, galactose, gulose,iodose and talose and the deoxypyranosyl group is derived from allose,glucose, galactose and gulose.

It has been found that by virtue of including amino acids andnicotinamide compounds as described herein skin lightening issynergistically increased, thus overcoming the drawback of cystine'slimited solubility.

In one embodiment, the composition of the invention is a leave-onnon-solid composition in the form of a personal care topical emulsion,lotion, gel, cream, or vanishing cream comprising skin lighteningadditive of cystine, glutamate (especially pyroglutamic acid or saltthereof, e.g. sodium pyroglutamate), glycine and nicotinamide, at pH of3.5 to 8.5, especially at pH of 5 to 8.

In one embodiment, the composition of the invention is a leave-onnon-solid composition in the form of a personal care topical emulsion,lotion, gel, cream, or vanishing cream comprising skin lighteningadditive of cystine, glutamate (especially pyroglutamic acid or saltthereof, e.g. sodium pyroglutamate), glycine, and isonicotinamide at pHof 3.5 to 8.5, especially at pH of 5 to 8.

In one embodiment, the composition of the invention is a leave-onnon-solid composition in the form of a personal care topical emulsion,lotion, gel, cream, or vanishing cream comprising skin lighteningadditive of cystine, glutamate (especially pyroglutamic acid or saltthereof, e.g. sodium pyroglutamate), glycine, and nicotinamide ribosideat pH of 3.5 to 8.5, especially at pH of 5 to 8.

In one embodiment, the composition of the invention is a leave-onnon-solid composition in the form of a personal care topical emulsion,lotion, gel, cream, or vanishing cream comprising skin lighteningadditive of cystine, glutamate (especially pyroglutamic acid or saltthereof, e.g. sodium pyroglutamate), glycine and N-methyl nicotinamideat pH of 3.5 to 8.5, especially at pH of 5 to 8.

Amounts

In one embodiment, cystine is included in an amount of from 0.001 to 2%,or in the alternative of from to 0.005 to 1%, or from 0.008 to 0.5%, orin the alternative from 0.008 to 0.4%. In one embodiment, glutamatesource (preferably pyroglutamate) is included in an amount of from 0.01to 10%, or in the alternative of from to 0.01 to 5%, or from 0.05 to 1%,or in the alternative from 0.05 to 0.5%. In one embodiment, glycinesource is included in an amount of from 0.01 to 10%%, or in thealternative of from to 0.01 to 5%, or from 0.05 to 1%, or in thealternative from 0.05 to 0.5%. In one embodiment, nicotinamide compoundis included in an amount of from 0.05% to 10%, or in the alternative offrom to 0.1 to 8%, or from 0.2 to 5%, or in the alternative from 0.2 to5%.

The amount of nicotinamide compound is by far pre-dominant compared tothe total amount of amino acids in the composition. In one embodimentthe weight ratio of nicotinamide to the total amino acid is from 20:1 to50:1. In one embodiment, the weight ratio is from 25:1 to 45:1.

Carrier

Compositions of this invention also include a cosmetically acceptablecarrier. Amounts of the carrier may range from 1 to 99.9%, preferablyfrom 70 to 95%, optimally from 80 to 90%. Among the useful carriers arewater, emollients, fatty acids, fatty alcohols, thickeners andcombinations thereof. The carrier may be aqueous, anhydrous or anemulsion. Preferably the compositions are aqueous, especially water andoil emulsions of the water-in-oil or oil-in-water type or multipleemulsions of the water-in-oil-in-water or oil-in-water-in-oil variety.Water when present may be in amounts ranging from 5 to 95%, preferablyfrom about 20 to about 70%, optimally from 35 to 60% by weight.

Emollient materials may serve as cosmetically acceptable carriers. Thesemay be in the form of silicone oils, natural or synthetic esters,hydrocarbons, alcohols and fatty acids. Amounts of the emollients mayrange anywhere from 0.1 to 95%, preferably between 1 and 50% by weightof the composition.

Silicone oils may be divided into the volatile and nonvolatile variety.The term “volatile” as used herein refers to those materials which havea measurable vapor pressure at ambient temperature. Volatile siliconeoils are preferably chosen from cyclic (cyclomethicone) or linearpolydimethylsiloxanes containing from 3 to 9, preferably from 5 to 6,silicon atoms. Nonvolatile silicone oils useful as an emollient materialinclude polyalkyl siloxanes, polyalkylaryl siloxanes and polyethersiloxane copolymers. The essentially nonvolatile polyalkyl siloxanesuseful herein include, for example, polydimethyl siloxanes withviscosities of from 5×10⁻⁶ to 0.1 m²/s at 25° C. Among the preferrednonvolatile emollients useful in the present compositions are thepolydimethyl siloxanes having viscosities from 1×10⁻⁵ to about 4×10⁻⁴m²/s at 25° C. Another class of nonvolatile silicones are emulsifyingand non-emulsifying silicone elastomers. Representative of this categoryis DimethiconeNinyl Dimethicone Crosspolymer available as Dow Corning9040, General Electric SFE 839, and Shin-Etsu KSG-18. Silicone waxessuch as Silwax WS-L (Dimethicone Copolyol Laurate) may also be useful.

Among the ester emollients are:

a) Alkyl esters of saturated fatty acids having 10 to 24 carbon atoms.Examples thereof include behenyl neopentanoate, isononyl isonanonoate,isopropyl myristate and octyl stearate.

b) Ether-esters such as fatty acid esters of ethoxylated saturated fattyalcohols.

c) Polyhydric alcohol esters. Ethylene glycol mono and di-fatty acidesters, diethylene glycol mono- and di-fatty acid esters, polyethyleneglycol (200-6000) mono- and di-fatty acid esters, propylene glycol mono-and di-fatty acid esters, polypropylene glycol 2000 monostearate,ethoxylated propylene glycol monostearate, glyceryl mono- and di-fattyacid esters, polyglycerol poly-fatty esters, ethoxylated glycerylmono-stearate, 1,3-butylene glycol monostearate, 1,3-butylene glycoldistearate, polyoxyethylene polyol fatty acid ester, sorbitan fatty acidesters, and polyoxyethylene sorbitan fatty acid esters are satisfactorypolyhydric alcohol esters. Particularly useful are pentaerythritol,trimethylolpropane and neopentyl glycol esters of C₁-C₃₀ alcohols.

d) Wax esters such as beeswax, spermaceti wax and tribehenin wax.

e) Sugar ester of fatty acids such as sucrose polybehenate and sucrosepolycottonseedate.

Natural ester emollients principally are based upon mono-, di- andtri-glycerides. Representative glycerides include sunflower seed oil,cottonseed oil, borage oil, borage seed oil, primrose oil, castor andhydrogenated castor oils, rice bran oil, soybean oil, olive oil,safflower oil, shea butter, jojoba oil and combinations thereof. Animalderived emollients are represented by lanolin oil and lanolinderivatives. Amounts of the natural esters may range from 0.1 to 20% byweight of the compositions.

Hydrocarbons which are suitable cosmetically acceptable carriers includepetrolatum, mineral oil, C₁₁-C₁₃ isoparaffins, polybutenes andespecially isohexadecane, available commercially as Permethyl 101A fromPresperse Inc.

Fatty acids having from 10 to 30 carbon atoms may also be suitable ascosmetically acceptable carriers. Illustrative of this category arepelargonic, lauric, myristic, palmitic, stearic, isostearic, oleic,linoleic, linolenic, hydroxystearic and behenic acids and mixturesthereof.

Fatty alcohols having from 10 to 30 carbon atoms are another usefulcategory of cosmetically acceptable carrier. Illustrative of thiscategory are stearyl alcohol, lauryl alcohol, myristyl alcohol, oleylalcohol and cetyl alcohol and mixtures thereof.

Thickeners or rheology modifiers can be utilized as part of thecosmetically acceptable carrier of compositions according to the presentinvention. Typical thickeners include crosslinked acrylates (e.g.Carbopol 982®), hydrophobically-modified acrylates (e.g. Carbopol1382®), polyacrylamides (e.g. Sepigel 305®), acryloylmethylpropanesulfonic acid/salt polymers and copolymers (e.g. Aristoflex HMB® andAVC®), cellulosic derivatives and natural gums. Among useful cellulosicderivatives are sodium carboxymethylcellulose, hydroxypropylmethocellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, ethylcellulose and hydroxymethyl cellulose. Natural gums suitable for thepresent invention include guar, xanthan, sclerotium, carrageenan, pectinand combinations of these gums. Inorganics may also be utilized asthickeners, particularly clays such as bentonites and hectorites, fumedsilicas, talc, calcium carbonate and silicates such as magnesiumaluminum silicate (Veegum®). Amounts of the thickener may range from0.0001 to 10%, usually from 0.001 to 1%, or from 0.01 to 0.5%.

Preferred are emollients that can be used, especially for productsintended to be applied to the face, to improve sensory properties andare chosen from the group of polypropylene glycol-14 butyl etherotherwise known as Tegosoft PBE, or PPG15 stearyl ether such as TegosoftE, other oils such as esters, specifically, isopropyl myristate,isopropyl palmitate, other oils could include castor oils andderivatives thereof.

Humectants of the polyhydric alcohol-type can be employed ascosmetically acceptable carriers. Typical polyhydric alcohols includeglycerol, polyalkylene glycols and more preferably alkylene polyols andtheir derivatives, including propylene glycol, dipropylene glycol,polypropylene glycol, polyethylene glycol and derivatives thereof,sorbitol, hydroxypropyl sorbitol, hexylene glycol, 1,3-butylene glycol,isoprene glycol, 1,2,6-hexanetriol, ethoxylated glycerol, propoxylatedglycerol and mixtures thereof. The amount of humectant may rangeanywhere from 0.5 to 50%, preferably between 1 and 15% by weight of thecomposition.

Skin moisturizers, e.g. hyaluronic acid and/or its precursor N-acetylglucosamine may be included. N-acetyl glucosamine may be found in sharkcartilage or shitake mushrooms and are available commercially fromMaypro Industries, Inc (New York). Other preferred moisturizing agentsinclude hydroxypropyl tri(C₁-C₃ alkyl)ammonium salts. These salts may beobtained in a variety of synthetic procedures, most particularly byhydrolysis of chlorohydroxypropyl tri(C₁-C₃ alkyl)ammonium salts. A mostpreferred species is 1,2-dihydroxypropyltrimonium chloride, wherein theC₁-C₃ alkyl is a methyl group. Amounts of the salt may range from 0.2 to30%, and preferably from 0.5 to 20%, optimally from 1% to 12% by weightof the topical composition, including all ranges subsumed therein.Ordinarily the C₁-C₃ alkyl constituent on the quaternized ammonium groupwill be methyl, ethyl, n-propyl, isopropyl or hydroxyethyl and mixturesthereof. Particularly preferred is a trimethyl ammonium group knownthrough INCI nomenclature as a “trimonium” group. Any anion can be usedin the quat salt. The anion may be organic or inorganic with provisothat the material is cosmetically acceptable. Typical inorganic anionsare halides, sulfates, phosphates, nitrates and borates. Most preferredare the halides, especially chloride. Organic anionic counter ionsinclude methosulfate, toluoyl sulfate, acetate, citrate, tartrate,lactate, gluconate, and benzenesulfonate. Still other preferredmoisturizing agents which may be used, especially in conjunction withthe aforementioned ammonium salts include substituted urea likehydroxymethyl urea, hydroxyethyl urea, hydroxypropyl urea;bis(hydroxymethyl) urea; bis(hydroxyethyl) urea; bis(hydroxypropyl)urea; N,N′-dihydroxymethyl urea; N,N′-di-hydroxyethyl urea;N,N′-di-hydroxypropyl urea; N,N,N′-tri-hydroxyethyl urea;tetra(hydroxymethyl) urea; tetra(hydroxyethyl) urea; tetra(hydroxypropylurea; N-methyl, N′-hydroxyethyl urea; N-ethyl-N′-hydroxyethyl urea;N-hydroxypropyl-N′-hydroxyethyl urea and N,N′dimethyl-N-hydroxyethylurea. Where the term hydroypropyl appears, the meaning is generic foreither 3-hydroxy-n-propyl, 2-hydroxy-n-propyl, 3-hydroxy-i-propyl or2-hydroxy-i-propyl radicals. Most preferred is hydroxyethyl urea. Thelatter is available as a 50% aqueous liquid from the National Starch &Chemical Division of ICI under the trademark Hydrovance. Amounts ofsubstituted urea that may be used in the topical composition of thisinvention range from 0.01 to 20%, or from 0.5 to 15%, or from 2 to 10%.When ammonium salt and substituted urea are used, in a most especiallypreferred embodiment at least from 0.01 to 25%, or from 0.2 to 20%, orfrom 1 to 15% humectant, like glycerine, is used. Further moisturizingagents for use herein include petrolatum and/or various aquaporinmanipulating actives and/or oat kernel flour.

pH of the Composition

In one embodiment, the pH of the personal care composition is between3.5 and 8.5. In some embodiments, the pH of the personal carecomposition is between pH 3.5 and pH 8. In some embodiments, the pH ofthe personal care composition is between pH 5 to pH 7.8. In someembodiments, the pH of the personal care composition is between 5 and7.5.

Preferred Optional Ingredients

In some embodiments, the personal care composition, and especially aleave-on skin cosmetic composition of the present invention containssun-screen. These are typically a combination of organic and inorganicsunscreens. It is particularly important to include both UV-A and UV-Bradiation sunscreens.

UV-B sunscreen oil may be selected from the class of cinnamic acid,salicylic acid, diphenyl acrylic acid, or derivatives thereof. The UV-Bsunscreen oil may include one or more of octyl salicylate,3,3,5-trimethylcyclohexyl 2-hydroxybenzoate, ethylhexyl salicylate,2-ethylhexyl 2-cyano-3,3-diphenyl-2-propenoate, or2-ethylhexyl-4-methoxycinnamate (also known as octyl methoxycinnamate or“OMC”). Such UV-B sunscreen oils are typically commercially available,such as Octisalate™ (octyl salicylate), Homosalate™(3,3,5-trimethyleyclohexyl 2-hydroxybenzoate), NeoHeliopan™ (a range oforganic UV filters including OMC (Neo Heliopan AV™) and ethylhexylsalicylate (Neo Heliopan OS™)), Octocrylene™ and Milestab 3039™(2-ethylhexyl-2-cyano-3,3-diphenyl-2-propenoate) or Parsol MCX™(2-ethylhexyl-4-methoxycinnamate). The amount of UV-B sunscreen oil inthe personal care composition may be 0.1 wt % to 20 wt %, or 0.2 wt % to10 wt %, or 0.5 wt % to 7 wt %, or 2 wt % to 6 wt %.

The personal care composition may further include a UV-B sunscreen thatis water-soluble. The water soluble UV-B sunscreen may also includephenylbezimidazole sulfonic acid (also known as ensulizole),4-aminobenzoic acid (also known as para-aminobenzoic acid or “PABA”), orboth.

The personal care composition of any one of the above embodiments mayfurther include 0.1 wt % to 10 wt % of a UV-A sunscreen oil. The UV-Asunscreen oil may include one or more of4-t-butyl-4′-methoxydibenzoylmethane (“avobenzone”),2-methyldibenzoylmethane, 4-methyl-dibenzoyl-ethane,4-isopropyldibenzoyl-methane, 4-tert-butyldibenzoylmethane,2,4-dimethyldibenzoylmethane, 2,5-dimethyldibenzoylmethane,4,4′-diisopropyldibenzoylmethane,2-methyl-5-isopropyl-4′-methoxy-dibenzoylmethane,2-methyl-5-tert-butyl-4′-methoxy-dibenzoylmethane,2,4-dimethyl-4′-methoxydibenzoylmethane,2,6-dimehyl-4-tert-butyl-4′methoxy-dibenzoylmethane,diethylaminohydroxybenzoyl hexyl benzoate, ecamsule, or methylanthranilate. The amount of UV-A sunscreen oil in the personal carecomposition may be 0.5 wt % to 7 wt %, or 1 wt % to 5 wt %.

Additional suitable sunscreen oils suitable for use in the personal carecomposition include those commercially available from BASF corporation:Uvinul T-150 (Ethylhexyl triazone; a UV-B sunscreen oil), Uvinul A Plus(Diethylamino hydroxybenzoyl hexyl benzoate; a UV-A sunscreen oil),Tinosorb S (bis-ethylhexyloxyphenol methoxyphenyl triazine; a UV-A andUV-B sunscreen oil), Tinosorb M (methylene bisbenzotriazolyltetramethylbutylphenol; a UV-A and UV-B sunscreen oil). Bisdisulizonedisodium may also be included in the personal care composition.

A particularly preferred combination of UV-A and UV-B sunscreen oils isavobenzone and 2-ethylhexyl-4-methoxycinnamate.

In some embodiments, the sunscreen is an inorganic sunscreen. Examplesof inorganic sunscreens suitable for use in the skin care composition ofthe present invention include, but are not limited to, microfinetitanium dioxide, zinc oxide, polyethylene and various other polymers.By the term “microfine” is meant particles of average size ranging from10 to 200 nm, alternatively from 20 to 100 nm. Amounts of the sunscreenwhen present in a skin care formulation according to some embodiments ofthe present invention may range from 0.1% to 30%, alternatively from 2%to 20%, alternatively from 4% to 10%.

Although selenium source may be included, it is preferably avoided intopical skin care compositions of the invention because it is considereda skin sensitizer under some regulatory regimes. Accordingly, the amountof selenium in the present compositions is from 0 to maximum 0.1%, or atmost 0.05%, optimally no more than 0.01%.

The inventive composition preferably includes a skin lighteningcompound, in addition to the skin lightening additive included herein,to obtain optimum skin lightening performance at an optimum cost.Illustrative substances are placental extract, lactic acid, resorcinols(4-substituted, 2,5-disubstituted, 4,5-disubstituted, and 4,6di-substituted, in particular 4-hexyl, 4-methyl, 4-butyl, 4-isopropyl,phenylethyl resorcinols), arbutin, kojic acid, ferulic acid,hydroquinone, resorcinol derivatives including di-substitutedresorcinols and combinations thereof. In one embodiment, such skinlightening compound is a tyrosinase inhibitor, most preferably acompound selected from the group consisting of kojic acid, hydroquinoneand other (non-4 substituted resorcinols). Also, dicarboxylic acidsrepresented by the formula HOOC—(CxHy)-COOH where x=4 to 20 and y=6 to40 such as azelaic acid, sebacic acid, oxalic acid, succinic acid,fumaric acid, octadecenedioic acid (e.g. Arlatone DC) or their salts ora mixture thereof, most preferably fumaric acid or salt thereof,especially di-sodium salt. It has been found that combination with 12HSAwith fumaric acid or salts thereof are particularly preferred,especially for skin lightening formulations. Amounts of these agents mayrange from about 0.1 to about 10%, preferably from about 0.5 to about2%. It is preferred that the skin lightening coactive according to theinvention is 12HSA or a resorcinol.

Another preferred ingredient of the inventive compositions is aretinoid. As used herein, “retinoid” includes all natural and/orsynthetic analogs of Vitamin A or retinol-like compounds which possessthe biological activity of Vitamin A in the skin as well as thegeometric isomers and stereoisomers of these compounds. The retinoid ispreferably retinol, retinol esters (e.g., C₂-C₂₂ alkyl esters ofretinol, including retinyl palmitate, retinyl acetate, retinylpropionate), retinal, and/or retinoic acid (including all-trans retinoicacid and/or 13-cis-retinoic acid), more preferably retinoids other thanretinoic acid. These compounds are well known in the art and arecommercially available from a number of sources, e.g., Sigma ChemicalCompany (St. Louis, Mo.), and Boerhinger Mannheim (Indianapolis, Ind.).Other retinoids which are useful herein are described in U.S. Pat. No.4,677,120, issued Jun. 30, 1987 to Parish et al.; U.S. Pat. No.4,885,311, issued Dec. 5, 1989 to Parish et al.; U.S. Pat. No.5,049,584, issued Sep. 17, 1991 to Purcell et al.; U.S. Pat. No.5,124,356, issued Jun. 23, 1992 to Purcell et al.; and U.S. Pat. No.Reissue 34,075, issued Sep. 22, 1992 to Purcell et al. Other suitableretinoids are tocopheryl-retinoate [tocopherol ester of retinoic acid(trans- or cis-), adapalene{6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid}, and tazarotene(ethyl 6-[2-(4,4-dimethylthiochroman-6-yl)-ethynyl]nicotinate).Preferred retinoids are retinol, retinyl palmitate, retinyl acetate,retinyl propionate, retinal and combinations thereof. The retinoid ispreferably substantially pure, more preferably essentially pure. Thecompositions of this invention may contain a safe and effective amountof the retinoid, such that the resultant composition is safe andeffective for regulating keratinous tissue condition, preferably forregulating visible and/or tactile discontinuities in skin, morepreferably for regulating signs of skin aging, even more preferably forregulating visible and/or tactile discontinuities in skin textureassociated with skin aging. The compositions preferably contain from0.005% to 2%, or from 0.01% to 2%, retinoid. Retinol is preferably usedin an amount of 0.01% to 0.15%; retinol esters are preferably used in anamount of from 0.01% to 2% (e.g., 1%); retinoic acids are preferablyused in an amount of 0.01% to 0.25%; tocopheryl-retinoate, adapalene,and tazarotene are preferably used in an amount of from 0.01% to 2%.

A variety of herbal extracts may optionally be included in compositionsof this invention. Illustrative are pomegranate, white birch (Betulaalba), green tea, chamomile, licorice and extract combinations thereof.The extracts may either be water soluble or water-insoluble carried in asolvent which respectively is hydrophilic or hydrophobic. Water andethanol are the preferred extract solvents.

Also included may be such materials as resveratrol, alpha-lipoic acid,ellagic acid, kinetin, retinoxytrimethylsilane (available from ClariantCorp. under the Silcare 1M-75 trademark), dehydroepiandrosterone (DHEA)and combinations thereof. Ceramides (including Ceramide 1, Ceramide 3,Ceramide 3B, Ceramide 6 and Ceramide 7) as well as pseudoceramides mayalso be utilized for many compositions of the present invention but mayalso be excluded. Amounts of these materials may range from 0.000001 to10%, preferably from 0.0001 to 1%.

The personal care composition may further include about 0.1 wt % toabout 8 wt % of a film forming polymer. Such film-forming polymersinclude, but are not limited to, polyalkyleneoxy terminated polyamides(e.g., INCI name: Polyamide-3, Polyamide-4), polyether polyamides (e.g.,INCI name: Polyamide-6), mixed acid terminated polyamides (e.g., INCIname: Polyamide-7), and ester terminated poly(ester-amides) (e.g., INCIname: Polyamide-8). Such film forming polymers may be synthesized or areavailable commercially, such as under the Sylvaclear™ line of productsby Arizona Chemical Company, LLC and the OleoCraft™ line of products byCroda International PLC. Film-forming polymers also include, but are notlimited to, the INCI named Polyester-5 (e.g., Eastman AQ™ 38 S Polymer),PPG-17/IPDI/DMPA Copolymer (e.g., Avalure™ UR 450 Polymer), AcrylatesCopolymer (e.g., Avalure™ AC 120 Polymer), and polysaccharides such asXilogel (tamarin gum), lotus bean gums, tara gum, beta glucan, pullulan,carboxymethyl cellulose, hydroxypropyl cellulose, sodium alginate,potato starch, carrageenan. The film forming polymer may includecombinations of any two or more of the polymers recited above. Theamount of film forming polymer in the personal care composition may be0.1 wt % to 8 wt %.

Preservatives can desirably be incorporated into the compositions ofthis invention to protect against the growth of potentially harmfulmicroorganisms. Suitable traditional preservatives for compositions ofthis invention are alkyl esters of para-hydroxybenzoic acid. Otherpreservatives which have more recently come into use include hydantoinderivatives, propionate salts, and a variety of quaternary ammoniumcompounds. Cosmetic chemists are familiar with appropriate preservativesand routinely choose them to satisfy the preservative challenge test andto provide product stability. Particularly preferred preservatives areiodopropynyl butyl carbamate, phenoxyethanol, caprylyl glycol, C₁₋₈parabens (especially, methyl paraben and/or propyl paraben),imidazolidinyl urea, sodium dehydroacetate and benzyl alcohol. Thepreservatives should be selected having regard for the use of thecomposition and possible incompatibilities between the preservatives andother ingredients in the emulsion. Preservatives are preferably employedin amounts ranging from 0.01% to 2%. An especially preferred combinationis octocrylene and caprylyl glycol, since caprylyl glycol has beendisclosed to enhance UVA and UVB protection.

Anti-fungal agents suitable for inclusion in personal care compositionsare well known to one of skill in the art. Examples include, but are notlimited to, climbazole, ketoconazole, fluconazole, clotrimazole,miconazole, econazole, etaconazole, terbinafine, salts of any one ormore of these (e.g., hydrochloride salts), zinc pyrithione, seleniumdisulfide, and combinations of any two or more thereof.

In some embodiments, the personal care compositions of the presentinvention include vitamins. Illustrative vitamins are Vitamin A(retinol), Vitamin B2, Vitamin B3 (niacin), Vitamin B6, Vitamin B12,Vitamin C, Vitamin D, Vitamin E, Vitamin K and Biotin. Derivatives ofthe vitamins may also be employed. For instance, Vitamin C derivativesinclude ascorbyl tetraisopalmitate, magnesium ascorbyl phosphate andascorbyl glycoside. Derivatives of Vitamin E include tocopheryl acetate,tocopheryl palmitate and tocopheryl linoleate. DL-panthenol andderivatives may also be employed. In some embodiments, the Vitamin B6derivative is Pyridoxine Palmitate. Flavonoids may also be useful,particularly glucosyl hesperidin, rutin, and soy isoflavones (includinggenistein, daidzein, equol, and their glucosyl derivatives) and mixturesthereof. Total amount of vitamins or flavonoids when present may rangefrom 0.0001% to 10%, alternatively from 0.001% to 10%, alternativelyfrom 0.01% to 10%, alternatively from 0.1% to 10%, alternatively from 1%to 10%, alternatively from 0.01% to 1%, alternatively from 0.1% to 0.5%.

In some embodiments, the personal care compositions of the presentinvention include an enzyme such as, for example oxidases, proteases,lipases and combinations thereof. In some embodiments, the personal carecompositions of the present invention includes superoxide dismutase,commercially available as Biocell SOD from the Brooks Company, USA.

In some embodiments, the personal care compositions of the presentinvention include desquamation promoters. In some embodiments, thepersonal care compositions of the present invention include desquamationpromoters at a concentration from 0.01% to 15%, alternatively from 0.05%to 15% alternatively from 0.1% to 15%, alternatively from 0.5% to 15%

Illustrative desquamation promoters include monocarboxylic acids.Monocarboxylic acids may be substituted or unsubstituted with a carbonchain length of up to 16. In some embodiments, the carboxylic acids arethe alpha-hydroxycarboxylic acids, beta-hydroxycarboxylic orpolyhydroxycarboxylic acids. The term “acid” is meant to include notonly the free acid but also salts and C₁-C₃₀ alkyl or aryl estersthereof and lactones generated from removal of water to form cyclic orlinear lactone structures. Representative acids include glycolic, lacticmalic and tartaric acids. In some embodiments, the salt is ammoniumlactate. In some embodiments, the beta-hydroxycarboxylic acid issalicylic acid. In some embodiments, the phenolic acids include ferulicacid, salicylic acid, kojic acid and their salts.

In some embodiments, the at least one additional component may bepresent from 0.000001% to 10%, alternatively from 0.00001% to 10%,alternatively from 0.0001% to 10%, alternatively from 0.001% to 10%,alternatively from 0.01% to 10%, alternatively from 0.1% to 10%,alternatively from 0.0001% to 1% by weight of the composition.Colorants, opacifiers or abrasives may also be included in compositionsof the present invention. The colorants, opacifiers or abrasives may beincluded at a concentration from 0.05% to 5%, alternatively between 0.1%and 3% by weight of the composition.

In some embodiments, the personal care product of the present inventionmay also include a peptide, such as, for example, the commerciallyavailable pentapeptide derivative-Matrixyl™, which is commerciallyavailable from Sederma, France. In another example, in some embodiments,the personal care product of the present invention may also includeCamosine.

The compositions of the present invention can comprise a wide range ofother optional components. The CTFA Cosmetic Ingredient Handbook, SecondEdition, 1992, which is incorporated by reference herein in itsentirety, describes a wide variety of non-limiting cosmetic andpharmaceutical ingredients commonly used in the topical cosmetic skincare industry, which are suitable for use in the compositions of thepresent invention. Examples include: antioxidants, binders, biologicaladditives, buffering agents, colorants, thickeners, polymers,astringents, fragrance, humectants, opacifying agents, conditioners,exfoliating agents, pH adjusters, preservatives, natural extracts,essential oils, skin sensates, skin soothing agents, and skin healingagents.

Form of the Composition

The compositions of the present invention are preferably non-solid. Thecompositions of the invention are preferably leave-on compositions. Thecompositions of the present invention are preferably leave-oncompositions to be applied to remain on the skin. These leave-oncompositions are to be distinguished from compositions which are appliedto the skin and subsequently removed either by washing, rinsing, wiping,or the like either after or during the application of the product.Surfactants typically used for rinse-off compositions havephysico-chemical properties giving them the ability to generatefoam/lather in-use with ease of rinse; they can consist of mixtures ofanionic, cationic, amphoteric, and nonionic. Surfactants used inleave-on compositions on the other hand are not required to have suchproperties. Rather, as leave-on compositions are not intended to berinsed-off they need to be non-irritating and therefore it is necessaryto minimize the total level of surfactant and the total level of anionicsurfactant in leave-on compositions. The total level of surfactant inthe inventive compositions is preferably from 1% to no more than 10%,more preferably below 8%, most preferably at most 5%, optimally at most3%.

In some embodiments, anionic surfactants are present in the leave-onskin care composition in an amount of 0.01% to at most 5% by weight ofthe composition, alternatively from 0.01% to 4% by weight of thecomposition, alternatively from 0.01%, to 3% by weight of thecomposition, alternatively from 0.01% to 2% by weight of thecomposition, alternatively substantially absent (less than 1%, or lessthan 0.1%, or less than 0.01%). In some embodiments, the total level ofsurfactant in the skin care compositions is no more than 10%,alternatively below 8%, alternatively at most 5%.

In some embodiments, the surfactant is selected from the groupconsisting of anionic, nonionic, cationic and amphoteric actives.

In some embodiments, nonionic surfactants are those with a C₁₀-C₂₀ fattyalcohol or acid hydrophobe condensed with from 2 to 100 moles ofethylene oxide or propylene oxide per mole of hydrophobe; C₂-C₁₀ alkylphenols condensed with from 2 to 20 moles of alkylene oxide; mono- anddi-fatty acid esters of ethylene glycol; fatty acid monoglyceride;sorbitan, mono- and di-C₈-C₂₀ fatty acids; and polyoxyethylene sorbitanas well as combinations thereof. In some embodiments, the non-ionicsurfactant is selected from the group consisting of alkylpolyglycosides, saccharide fatty amides (e.g. methyl gluconamides) andtrialkylamine oxides.

Amphoteric surfactants suitable in skin care compositions according tosome embodiments of the present invention include cocoamidopropylbetaine, C₁₂-C₂₀ trialkyl betaines, sodium lauroamphoacetate, and sodiumlaurodiamphoacetate.

Anionic surfactants suitable in skin care compositions according to someembodiments of the present invention include soap, alkyl ether sulfatesand sulfonates, alkyl sulfates and sulfonates, alkylbenzene sulfonates,alkyl and dialkyl sulfosuccinates, C₈-C₂₀ acyl isethionates, C₈-C₂₀alkyl ether phosphates, C₈-C₂₀ sarcosinates, C₈-C₂₀ acyl lactylates,sulfoacetates and combinations thereof.

The compositions of the present invention are typically in the form ofemulsions, which may be oil-in-water, or water-in-oil. In someembodiments the personal care compositions are vanishing creams andcreams or lotions based on an oil-in-water emulsion. Vanishing creambase is one which comprises 5 to 40% fatty acid and 0.1 to 20% soap. Insuch creams, the fatty acid is preferably substantially a mixture ofstearic acid and palmitic acid and the soap is preferably the potassiumsalt of the fatty acid mixture, although other counterions and mixturesthereof can be used. The fatty acid in vanishing cream base is oftenprepared using hystric acid which is substantially (generally about 90to 95%) a mixture of stearic acid and palmitic acid. A typical hystricacid comprises about 52-55% palmitic acid and 45-48% stearic acid of thetotal palmitic-stearic mixture. Thus, inclusion of hystric acid and itssoap to prepare the vanishing cream base is within the scope of thepresent invention. It is particularly preferred that the compositioncomprises higher than 7%, preferably higher than 10%, more preferablyhigher than 12% fatty acid. A typical vanishing cream base is structuredby a crystalline network and is sensitive to the addition of variousingredients.

In one embodiment, the personal care composition is formulated as awater-in-oil emulsion with cystine substantially solubilized in theaqueous phase. In one embodiment, the personal care composition isformulated as a water-in-oil emulsion with cystine in the aqueousdroplets, with at least 90% of the droplets having a diameter in therange of from 100 nm to 20 microns, or in the alternative from 200 nm to20 microns, or to 10 microns.

In some embodiments, in addition to containing the skin lighteningadditive, the personal care composition is formulated as a facial mask.In some embodiments, in addition to containing skin lightening additive,the personal care composition is formulated as a facial mask accordingto the formulations described in U.S. Pat. No. 5,139,771 In someembodiments, in addition to containing the skin lightening additive, thepersonal care composition is formulated as a facial mask according tothe formulations described in U.S. Pat. No. 4,933,177. In someembodiments, in addition to containing the GSH precursor, the personalcare composition is formulated as a facial mask according to theformulations described in U.S. Pat. No. 6,001,367.

In some embodiments, in addition to containing the skin lighteningadditive, the personal care composition is formulated as a shampoo. Insome embodiments, the personal care compositions of the presentinvention are formulated as a deodorant. In some embodiments, inaddition to containing skin lightening additive, the personal carecomposition is formulated as a deodorant according to the formulationsdescribed in U.S. Pat. No. 7,282,471. In some embodiments, the personalcare compositions of the present invention are formulated as anantiperspirant. In some embodiments, in addition to containing skinlightening additive, the personal care composition is formulated as anantiperspirant according to the formulations described in U.S. Pat. No.7,282,471.

In some embodiments, the personal care compositions of the presentinvention are formulated as a single use personal care toweletteproduct. In some embodiments, in addition to containing the skinlightening additive, the personal care composition is formulated as asingle use personal care towelette product according to the formulationsdescribed in U.S. Pat. No. 7,282,471.

In some embodiments, the personal care compositions of the presentinvention are formulated as a soap bar. In some embodiments, in additionto containing the skin lightening additive, the personal carecomposition is formulated as a soap bar according to the formulationsdescribed in U.S. Pat. No. 7,282,471.

Methods of Making Skin Care Compositions

In some embodiments, skin care compositions according to the presentinvention can be made by:

-   -   a. mixing all water soluble ingredients including preservatives,        thickening polymer, optionally glycerine, and water;    -   b. heating the mixture to a temperature of 70-90° C.;    -   c. mixing all the oil soluble ingredients and the compound of        formula (1) to a temperature of 70-90° C.;    -   d. adding the mixed oil soluble ingredients to the heated        mixture of water soluble ingredients, and mixing via agitation,        maintaining the mixture at a temperature of 70-90° C.; and    -   e. cooling the mixture to room temperature, whilst mixing.

In some embodiments the personal care compositions of the invention areprepared by making an emulsion:

-   -   a. solubilizing cystine at the desired level in high pH (9 to        14, or 9 to 12) aqueous solution    -   b. preparing a macroemulsion in oil with this solution with an        emulsifier, then    -   c. adding, with mixing, an acidic aqueous solution to obtain an        emulsion with pH within a neutral range required for the topical        composition and, lastly,    -   d. subjecting the emulsion to high shear, or homogenization, or        sonolation step e.g. via a homogenizer such as Nano DeBee        homogenizer of BEE International (Massachusetts, USA) or a        Sonolator homogenizer manufactured by Sonic Corporation        (Connecticut, USA), to produce a homogeneous neutral pH range        final emulsion with more than 90% of the droplets having a        diameter in the size range of from 100 nm to 20 microns.        Method of Using the Skin Care Compositions

In some embodiments, the skin care composition is topically applied tohuman skin. In some embodiments, the skin care composition provides atleast one benefit, selected from the group consisting of: skinconditioning, skin smoothening, reduction of wrinkled or aged skin,reduction of inflammation of the skin, reduction of dryness, reductionof age spots, an reduction of sun burn, and lightening of the skin.

In some embodiments, a small quantity of the skin care composition, forexample from 1 to 5 ml, is applied to exposed area of the skin, from asuitable container or applicator and, if necessary, it is then spreadover and/or rubbed into the skin using the hand or fingers or a suitabledevice.

Reference is now made to the following examples, which together with theabove descriptions illustrate some embodiments of the invention innon-limiting examples.

EXAMPLES Experimental Methods

Powders of the following amino acids (glutamine and glycine) werepurchased from Sigma, and individual stock solutions of each amino acidprepared by reconstitution of the powder in water (pH 7). Cystine(Sigma) stock solutions were generated in 0.5M sodium hydroxide (pH 12)as cystine is poorly soluble in neutral solutions. To generate themixture henceforth described as GAP, appropriate volumes of three aminoacids (glutamine, cystine, and glycine) were combined in Hank's BalancedSalt Solution (Sigma) such that the glutamine, cystine, and glycine werein a 0.5:1:1 weight ratio. The specific concentrations used in eachassay are referenced below. Powders of cystine esters, includingditert-butyl L-cystinate dihydrochloride (DTBC) and diethyl L-cystinatedihydrochioride (DEC) were purchased from Bachem; L-Cystine dimethylester dihydrochioride (COME) was from Sigma. The cystine esters wereprepared in water and stock solutions were diluted in Hank's BalancedSalt Solution (HBSS). The specific concentrations used in each assay arereferenced below.

Additional test reagents: nicotinamide (Sigma-Aldrich), niacin(Himedia), nicotinamide riboside (Chromadex), isonicotinamide(Sigma-Aldrich), picolinamide (Sigma-Aldrich), n-methyl-nicotinamide(Sigma-Aldrich). Nicotinamide and derivatives/related compounds weresolubilized in water.

Melanin Content Assay

Human primary melanocytes (Cascade Biologics, now ThermoFisherScientific) were grown in melanocytes growth medium (MGM) with humanmelanocyte growth supplement (both media components from ThermoFisherScientific). Melanocytes were seeded at 5×10⁴ cells/well in 24well-plates and incubated in a humidified incubator at 37° C. with 5%CO₂ atmosphere. After 24 hours of incubation, cell cultures were treatedwith the GAP amino acids or additional test reagents above-described,alone or in combination, as described in examples below. The vehiclecontrol consisted of cells treated with the vehicle (0.002 mM NaOH)alone. After treatment, cells were again incubated for 72 hours in ahumidified incubator at 37° C. with 5% CO2 atmosphere. At the end of the72 hour incubation, the culture medium was replaced with 120 uL/well ofmelanin content assay reagent (10% DMSO in 1M sodium hydroxide) andincubated for 1 hour at 60° C. in a shaker incubator. The supernatantwas then transferred to a 384 well plate. The absorbance was measured byspectrophotometric analysis at 405 nm with a micro plate reader (GEniosPro, Tecan).

The spectrophotometric optical density at 405 nm for untreated cells (noactive) was considered as 100% melanin content. Relative melanin contentfor treated samples was calculated with normalization based on theuntreated (media/vehide) control.

Tyrosinase Activity Assay

Human primary melanocytes (Cascade Biologics, now ThermoFisherScientific) were grown in melanocytes growth medium (MGM) with humanmelanocyte growth supplement (both media components from ThermoFisherScientific). Melanocytes were seeded at 1×10⁴ cells/well in a 96 wellsplate and cultures left undisturbed for 24 hours in a 5% CO₂ humidifedincubator at 37° C. At 24 hrs post-seeding, cells were treated with GAPamino acids or additional test reagents above-described, alone or incombination, as described in examples below and left undisturbed foranother 72 hours. Subsequently, cell viability was assessed and thecells were then lysed and progressed for determination of in situtyrosinase activity. Cultures were rinsed twice with 1×phosphate-buffered saline and lysed with 40 uL of 0.5% TritonX 100 for 1hr on an ice bed. In situ tyrosinase activity was visualized by additionof 60 μl of 50 mM potassium phosphate buffer (pH 6.8) containing 2 mMDOPA (3,4 dihydroxy phenylalanine) and 4 mM MBTH reagent(3-Methyl-2-Benzothiazolinone hydrazone hydrochloride) for 1 hour at 37°C. The reaction was stopped by the addition of 100 uL of ice-cold 10%tricholoracetic acid and then centrifuged at approximately 300 g for 10minutes at 4° C. The soluble supernatant was separated from the pelletand the optical density read in a TECAN plate-reader (540 nm filter).The spectrophotometric optical density at 540 nm for untreated cells(media/vehicle) is considered as 100% tyrosinase activity. Tyrosinaseactivity is expressed after correction for cell numbers(activity/viability) and represented as % control.

Glutathione Assay

Human Keratinocytes (Promocell, Heidelberg, Germany) were maintained inEpiLife® medium containing 60 uM calcium chloride and 1% HumanKeratinocyte Growth Supplement (both media components from ThermoFisherScientific) in a humidified incubator with an atmosphere containing 5%CO₂ at 37° C. The medium was refreshed every 2-3 days. Subsequently,cells were trypsinized at 90% confluency and seeded at a density of1×10⁴ per well into 96-well plates with white wall and clear bottom. Oneor two days after seeding, cell medium was replaced with Hank's BalancedSalt Solution (HBSS), and keratinocytes were pre-treated with GAP (or0.12-0.240 mM sodium hydroxide vehicle control, pH 7.5) alone or incombination with additional test reagents described above or L-cystineesters alone for 1-2 hours. The concentration of all amino acidsconstituting the GAP mixture used in this assay are designated in thedata tables, and fully described in the abbreviations list below.

After one or two hours of pre-treatment with GAP or additional testreagents, alone or in combination, keratinocytes were then challengedwith 25 uM menadione (Sigma-Aldrich), a known inducer of oxidativestress. After 18-20 hours, cells were harvested and analyzed for totalglutathione levels using a commercially available kit (GSH-GSSG GLoAssay, Promega), a luminescence-based system for the detection andquantification of total glutathione in cultured cells. In summary, aftercell treatment, the media was removed and replaced with a cell lysisreagent for 5 minutes at 20-25° C.; note, all remaining steps were alsoconducted at 20-25° C. Next, a luciferase generation reagent was addedto each well and incubated for 30 minutes. Following this step, aluciferin detection reagent was added to each well and plates wereincubated for 15 minutes. Finally, plates were then read forluminescence in a FlexStation 3 plate reader (Molecular Devices). Totalglutathione levels were calculated after interpolation of glutathioneconcentrations from a standard curve. Experimental conditions weretypically conducted in at least triplicate determinations. Statisticalsignificance was calculated using 1-way ANOVA. Percent protection wascalculated by using the calculated glutathione levels from eachexperiment in the following equation:

${\frac{\left( {{Test}\mspace{14mu}{Sample}} \right) - \left( {{{vehicle}\mspace{14mu}{control}} + {menadione}} \right)}{{vehicle}\mspace{14mu}{control}} \times 100\%} = {\%\mspace{14mu}{protection}}$Reactive Oxygen Species (Ros) Assay

Human Keratinocytes (Promocell, Heidelberg, Germany) were maintained inEpiLife® keratinocyte medium containing 60 uM calcium chloride and 1%Human Keratinocyte Growth Supplement (HKGS) in a humidified incubatorwith an atmosphere containing 5% CO2 at 37° C. The medium was refreshedevery other day. Subsequently, cells were trypsinized at 90% confluencyand seeded at a density of 1-2×10⁴ per well into 96-well plates withblack wall and clear bottom. On the second day after seeding, cellmedium was replaced with Hank's Balanced Salt Solution (HBSS) with orwithout menadione (10-25 uM), GAP, GAP vehicle (0.2 mM NaOH, pH 7.5),above-described additional test reagents, or combinations of GAP withadditional test reagents or L-cystine esters alone, and incubated foradditional 18 hours. For ROS detection, CellROX green (Life Tech, ThermoFisher Scientific, Rockford, USA) reagent was added into each well to afinal concentration of 15-25 uM and incubated for additional 2-4 hoursat 37° C. in a humidified incubator. The ROS fluorescence was detectedusing a Tecan microplate reader (Excitation/Emission=490/525). RelativeROS production was calculated with normalization based on the vehiclecontrol treatment which was set to 100%. Where indicated, percentprotection was calculated as a comparison to menadione alone treatment,using the measured relative fluorescent units in the following equation:

${\frac{\left( {{{V{ehicle}}\mspace{14mu}{control}} + {Menadione}} \right) - \left( {{Test}\mspace{14mu}{sample}} \right)}{\left( {{{vehicle}\mspace{14mu}{control}} + {menadione}} \right)} \times 100\%} = {\%\mspace{14mu}{protection}}$

ROS levels were evaluated together with cell viability because it ispossible to get a false negative for ROS if treatment is so toxic, thatat the time of assay, cells are dead (and there are no longer anydetectable ROS). Decrease in ROS levels is meaningful if cells are stillviable.

Cell Viability Assay

Human Keratinocytes (Promocell, Heidelberg, Germany) were maintained inEpiLife® keratinocyte medium containing 60 uM calcium chloride and 1%Human Keratinocyte Growth Supplement (HKGS). The medium was refreshedevery other day.

Subsequently, cells were trypsinized at 90% confluency and seeded at adensity of 2×10⁴ per well into 96-well transparent tissue cultureplates. On the second day after seeding, cell medium was replaced withtreatments as described above in ROS assay section. After 18 hours, CellCulture Kit-8 (CCK-8) reagent (Dojindo, Kumamoto, Japan) was diluted1:10 in HBSS and incubated with cells for 4 h at 37° C. in a humidifiedincubator. Optical absorption at 450 nm was measured using a TecanSafire2 plate reader. Relative viability was calculated withnormalization based on the vehicle control treatment, which was set to100%.

Where indicated, percent protection was calculated as a comparison tomenadione alone treatment, using the measured relative absorbance unitsin the following equation:

${\frac{{{Test}\mspace{14mu}{Sample}} - \left( {{{vehicle}\mspace{14mu}{control}} - {menadione}} \right)}{\left( {{{vehicle}\mspace{14mu}{control}} + {menadione}} \right)} \times 100\%} = {\%\mspace{14mu}{protection}}$

Abbreviations in the Examples are as follows:

mM=millimolar

uM=micromolar

uL=micro liter

GAP=glutamine (32 uM), cystine (40 uM), glycine (129 uM) except where

otherwise denoted below.

GAP 10=8 uM sodium pyroglutamic acid, 10 uM cystine, 32 uM glycine

GAP 20=16 uM sodium pyroglutamic acid, 20 uM cystine, 64 uM glycine

GAP 60=48 uM sodium pyroglutamic acid, 60 uM cystine, 192 uM glycine

HR=4-hexylresorcinol

DEC=Diethyl L-cystinate dihydrochloride

CDME=L-Cystine dimethyl ester dihydrochloride

DTBC=Ditert-butyl L-cystinate dihydrochloride

Example 1

Example 1 investigated the skin lightening potential of the inventivecompositions. The results that were obtained are summarized in Table 1Athrough 1E.

TABLE 1A Melanin synthesis inhibition Sample Mean of % Inhibition AMedia Control  0 B Vehicle Control  0 Test samples C HR (10 uM) 35¹ DGAP  1 E GAP⁴ 14¹ F Nicotinamide (10 mM) 10¹ G Nicotinamide (5 mM)  9¹ 1GAP + Nicotinamide (10 mM) 27^(1, 2, 3) 2 GAP + Nicotinamide (5 mM)14^(1, 2, 3) Statistically significant improvement: ¹p < 0.05 comparedto media and vehicle control ²p < 0.05 compared to GAP (sample D) ³p <0.05 compared to Nicotinamide alone (at equivalent dose) ⁴amino acidconcentrations: glutamine (954 uM), cystine (1194 uM), glycine (129 uM)

TABLE 1B Tyrosinase inhibition Sample Mean of % Inhibition A MediaControl  0 B Vehicle Control  0 Test Samples C HR (10 uM) 67¹ D GAP  9¹E Nicotinamide (10 mM) 24¹ F Nicotinamide (5 mM) 16¹ 1 GAP +Nicotinamide (10 mM) 42^(1, 2, 3) 2 GAP + Nicotinamide (5 mM) 20¹Statistically significant improvement: ¹p < 0.05 compared to media andvehicle control ²p < 0.05 compared to GAP ³p < 0.05 compared toNicotinamide alone (at equivalent dose)

TABLE 1C Melanin synthesis inhibition Mean of % Sample Inhibition AMedia Control  0 B Vehicle Control  0 Test Samples C HR (10 μM) 26¹ DN-methyl Nicotinamide (10 mM)  7¹ E N-methyl Nicotinamide (5 mM)  0 FGAP  2 1 GAP + N-methyl Nicotinamide (10 mM) 12^(1,2,3) 2 GAP + N-methylNicotinamide (5 mM)  4¹ Statistically significant improvement: ¹p < 0.05compared to media and vehicle control ²p < 0.05 compared to GAP ³p <0.05 compared to N-methyl Nicotinamide alone (at equivalent dose)

TABLE 1D Melanin synthesis inhibition Mean of % Sample Inhibition AMedia Control  0 B Vehicle Control  0 Test Samples C HR (10 uM) 32¹ DGAP −1 E Isonicotinamide (10 mM) 20¹ F Isonicotinamide (5 mM)  4¹ 1GAP + Isonicotinamide (10 mM) 25^(1,2) 2 GAP + Isonicotinamide (5 mM)11^(1,2,3) Statistically significant improvement: ¹p < 0.05 compared tomedia and vehicle control ²p < 0.05 compared to GAP ³p < 0.05 comparedto iso-nicotinamide alone (at equivalent dose)

TABLE 1E Melanin synthesis inhibition Mean of % Sample Inhibition AMedia Control  0 B Vehicle Control  0 Test Samples C HR (10 uM) 28¹ DGAP  1 E Nicotinamide Riboside (2.5 uM)  9¹ F Nicotinamide Riboside (1uM)  4¹ 1 GAP + Nicotinamide Riboside (2.5 uM)  9^(1,2) 2 GAP +Nicotinamide Riboside (1 uM)  8^(1,2,3) Statistically significantimprovement: ¹p < 0.05 compared to media and vehicle control ²p < 0.05compared to GAP ³p < 0.05 compared to nicotinamide riboside alone (atequivalent dose)

In Tables 1A through 1E, samples marked by alphabetical characters wereoutside the scope of the invention. Numerically marked samples werewithin the scope of the invention. Sample C in Tables 1A through 1E wasa positive control as it employed 4-hexyl resorcinol, a known highlyeffective skin lightening agent. Overall, it can be seen from theresults in Tables 1A-1E that combination of nicotinamide compoundswithin the scope of the invention with GAP amino acids resulted insynergistic improvement (inhibition of melanin synthesis and tyrosinaseinhibition) compared to the results achieved with either thenicotinamide compound or GAP alone.

Comparative Example 2

Example 2 investigated the skin lightening potential of combinations ofGAP amino acids with either picolinamide (structurally similar moleculeto nicotinamide) or niacin (nicotinic acid)—both outside the scope ofthe invention. The results that were obtained are summarized in Tables2A and 2B.

TABLE 2 Melanin synthesis inhibition Sample Mean of % Inhibition A MediaControl  0 B Vehicle Control  0 Test Samples C HR (10 uM) 36¹ D GAP −1 EPicolinamide (5 mM)  6 F Picolinamide (10 mM) 32¹ G GAP + Picolinamide(10 mM) 31^(1,2) H GAP + Picolinamide (5 mM) 16^(1,2) Statisticallysignificant improvement: ¹p < 0.05 compared to media and vehicle control²p < 0.05 compared to GAP

TABLE 2B Melanin Synthesis inhibition Mean of % Sample Inhibition AMedia Control  0 B Vehicle Control  0 Test Sammples C HR (10 uM) 32¹ DGAP  1 E Niacin (5 mM) −7 F Niacin (10 mM) 14¹ G GAP + Niacin (10 mM) −5H GAP + Niacin (5 mM) −5 Statistically significant improvement: ¹p <0.05 compared to media and vehicle control

It can be seen from the results in Tables 2A and 2B that combination ofGAP amino acids with either picolinamide or niacin (both outside thescope of the invention) did not result in synergistic improvement(inhibition of melanin synthesis) compared to the results achieved witheither the nicotinamide compound or GAP alone.

Example 3

Example 3 evaluated amino acids constituting GSH building blocks forpotentiating intracellular GSH production. Results that were obtainedare summarized in Tables 3A In Tables 3B through 3D the efficacy ofvarious cystine esters was also tested.

TABLE 3A Glutathione Synthesis % Protection (improvement vs. Mean (uMvehicle control + Sample glutathione) menadione) A Vehicle Control 1.75B Vehicle Control + 0.07¹   0¹ menadione Test Samples C GAP 10 +menadione 1.34^(1,2)  72^(1,2) D GAP 20 + menadione 4.61² 259²Statistically significant decrease: ¹p < 0.05 compared to HR + GAP10 +menadione Statistically significant improvement: ²p < 0.05 compared tovehicle control + menadione

TABLE 3B Glutathione Syntheiss % Protection (improvement vs. Mean (μmvehicle control + Sample glutathione) menadione) A Vehicle control 2.73B Vehicle control + Menadione 0.18¹  0 C DEC (40 uM) + Menadione0.54^(1,2) 13^(1,2) D DEC (80 uM) + Menadione 2.72² 93² Statisticallysignificant decrease: ¹p < 0.05 compared to vehicle controlStatistically significant improvement: ²p < 0.05 compared to vehiclecontrol + menadione

TABLE 3C Glutathione Synthesis % Protection (improvement vs. Mean (μmvehicle control + Sample glutathione) menadione) A Vehicle control 2.73B Vehicle control + Menadione 0.18¹ 0 C DTBC (40 uM) + Menadione 0.17¹0¹ D DTBC (80 uM) + Menadione 0.19¹ 1¹ Statistically significantdecrease: ¹p < 0.05 compared to vehicle control

TABLE 3D Glutathione Synthesis % Protection (improvement vs. Mean (μmvehicle control + Sample glutathione) menadione) A Vehicle control 2.96B Vehicle control + Menadione 0.18¹  0 C CDME (80 uM) + Menadione1.09^(1,2) 31^(1,2) Statistically significant decrease: ¹p < 0.05compared to vehicle control Statistically significant improvement: ²p <0.05 compared to vehicle control + menadione

Example 4

Example 4 evaluated amino acids constituting GSH building blocks forimproved reduction in oxygen species. Results that were obtained aresummarized in Table 4A In Tables 4B through 4D the efficacy of variouscystine esters was also tested.

TABLE 4A Reduction in Oxygen Species Mean ROS % protection % Protectionproduction (improvement Cell (improvement (% of vs vehicle viability vsvehicle vehicle control + (% of control + Sample control) menadione)control) menadione) A Vehicle 100.0 100.0 Control B Vehicle 504.8¹ 54.8¹ Control + Menadione Test Samples C Menadione 171.5^(1,2)66.02^(1,2)  92.7^(1,2) 69.11^(1,2) GAP 60 Statistically significantdifference: ¹p < 0.05 compared to vehicle control Statisticallysignificant difference: ²p < 0.05 compared to vehicle control +menadione

TABLE 4B Reduction in Reactive Oxygen Species ROS % Protection %Protection inhibition (improvement Cell (improvement (% of vs. vehicleviability vs vehicle vehicle control + (% of control + Sample control)menadione) control) menadione) Vehicle control 100 100 Vehicle control +375.5¹  73.7¹ Menadione DEC (20 uM) + 232.8^(1,2) 38.0^(1,2) 109.8²48.9² Menadione DEC (40 uM) + 211.9^(1,2) 43.6^(1,2) 127.3^(1,2)72.7^(1,2) Menadione DEC (80 uM) + 233.8^(1,2) 37.7^(1,2) 131.5^(1,2)78.3^(1,2) Menadione DEC (160 uM) + 253.8^(1,2) 32.4^(1,2) 122.3^(1,2)65.9^(1,2) Menadione Statistically significant difference: ¹p < 0.05compared to vehicle control Statistically significant difference: ²p <0.05 compared to vehicle control + menadione

TABLE 4C Reduction in Oxygen Species % Protection Cell % protection ROS(improvement viability (improvement inhibition vs. vehicle (% of vs.vehicle (% of vehicle control + vehicle control + Sample control)menadione) control) menadione) Vehicle control 100 100 Vehicle control +375.5¹  73.7¹ Menadione DTBC (20 uM) + 367.0¹  2.2  78.1¹   6.0¹Menadione DTBC (40 uM) + 323.7^(1, 2) 13.8^(1, 2)  75.9¹   3.0¹Menadione DTBC (80 uM) + 268.7^(1, 2) 28.4^(1, 2)  73.6¹ −0.1¹ MenadioneStatistically significant difference: ¹p < 0.05 compared to vehiclecontrol Statistically significant difference: ²p < 0.05 compared tovehicle control + menadione

TABLE 4D Reduction in Oxygen Species ROS % Protection Cell % protectioninhibition (improvement viability (improvement (% of vs. vehicle (% ofvs. vehicle vehicle control + vehicle control + Sample control)menadione) control) menadione) Vehicle control 100 100 Vehicle control +131.8¹  69.8¹ Menadione CDME (20 uM) + 107.8² 18.2²  90.9^(1,2)30.2^(1,2) Menadione CDME (40 uM) + 111.3^(1,2) 15.5^(1,2)  93.1^(1,2)33.4^(1,2) Menadione CDME (80 uM) + 114.3^(1,2) 13.3^(1,2)  87.0^(1,2)24.6^(1,2) Menadione CDME (160 uM) +  97.9² 25.7² 105.9^(1,2) 51.7^(1,2)Menadione Statistically significant difference: ¹p < 0.05 compared tovehicle control Statistically significant difference: ²p < 0.05 comparedto vehicle control + menadione

Example 5

Personal care formulations according to the present invention areillustrated in the Tables below. All numbers in the Tables representweight % in the composition.

TABLE I Oil-in-water formulations, lotions, and creams OW-1 OW-2 OW-3OW-4 OW-5 Water To 100 To 100 To 100 To 100 To 100 Glycerine     0-40    1-40     1-5     1-10     1-40 Propylene glycol     0-5     0-5Butylene glycol     0-5     0-5     0-5 Carbomer     0-2  0.03-1Ammonium     0-1  0.03-1  0.01-1 Acryloyl dimethyl taurate/VP copolymerStyrene/     0-1  0.01-1 Acrylates copolymer Xanthan Gum     0-1  0.01-1EDTA  0.01-0.01  0.01-0.01  0.01-1  0.01-1  0.01-1 Preservative  0.02-2 0.02-2  0.02-2  0.02-2  0.02-2 Titanium oxide     0-10  0.01-10 0.01-10  0.01-10  0.01-10 Colorant/     0-5     0-5     0-5     0-5    0-5 Pigment Triethanol     0-3  0.01-3  0.01-3  0.01-3  0.01-3amine/Sodium Hydroxide/ potassium Hydroxide Stearic acid     0-5  0.01-5 0.01-5  0.01-5  0.01-5 Isopropyl     0-10  0.01-10 MyristateCapric/Caprylic     0-10  0.01-10 Triglyceride C12-C15 alkyl     0-10 0.01-10 benzoate Mineral oil     0-10  0.01-10 Glyceryl stearate    0-5  0.01-5 Steareth-2     0-5  0.01-5  0.01-5 Steareth-21     0-5 0.01-5 Peg100 Stearate     0-5  0.01-2  0.01-5 Potassium Cetyl     0-5 0.01-2 Phosphate Tween20     0-5  0.01-5 Cetyl alcohol     0-4  0.01-4 0.01-4 Dicaprylyl     0-5  0.01-5 carbonate Ethyl hexyl     0-6  0.01-6methoxy- cinnamate Butyl     0-3  0.01-3  0.01-3  0.01-3 Methoxy-dibenzoyl- methane Ensulizole     0-4  0.01-4 Octinoxate     0-7.5Octisalate     0-5  0.01-5  0.01-5 Octocrylene     0-10  0.01-10 0.01-10 Homosalate     0-10  0.01-10 Dimethicone     0-10  0.01-10 0.01-10 Cyclomethicone     0-15  0.01-15 Fragrance     0-2     0-2    0-2     0-2     0-2 Glutamine/  0.01-10  0.01-10  0.01-10  0.01-10 0.01-10 Sodium PCA Glycine  0.01-10  0.01-10  0.01-10  0.01-10  0.01-10Cystine 0.001-2 0.001-2 0.001-2 0.001-2 0.001-2 Nicotinamide  0.05-10 0.05-10 Nicotinamide  0.05-10 riboside Isonicotinamide  0.05-10 0.05-10 N-methyl  0.05-10 Nicotinamide Nicotinyl myristate

TABLE II Water-in-oil topical lotions or creams WO-1 WO-2 WO-3 WO-4Water To 100 To 100 To 100 To 100 Glycerine     0-70     1-70     1-70Propylene glycol     0-5  0.01-5 Butylene glycol     0-5  0.01-5  0.01-5Disteardimonium Hectorite  0.01-1  0.01-1 EDTA  0.01-.01  0.01-1  0.01-1 0.01-1 Preservative  0.02-2  0.02-2  0.02-2  0.02-2 TiO2     0-10 0.01-10  0.01-10  0.01-10 Colorant/pigment     0-5     0-5     0-5    0-5 TEA/Sodium Hydroxide/     0-3  0.01-3  0.01-3  0.01-3 potassiumHydroxide Stearic acid     0-5  0.01-5 Isopropyl Myristate     0-10Capric/Caprylic     0-10  0.01-10 Triglyceride C12-C15 alkyl benzoate    0-10  0.01-10 Mineral oil     0-10 Glyceryl stearate     0-5Dimethicone copolyol     0-5  0.01-5  0.01-5 Cetyl PEG/PPG-10/1     0-5 0.01-5 Dimethicone Steareth-2     0-2 Sucrose Distearate     0-2 0.01-2 Cetyl alcohol     0-2  0.01-2  0.01-2 Ethyl hexyl     0-6 0.01-6 methoxycinnamate Butyl     0-3  0.01-3  0.01-3  0.01-3Methoxydibenzoylmethane Ensulizole     0-4  0.01-4 Octinoxate     0-7.5Octisalate     0-5  0.01-5  0.01-5 Octocrylene     0-10  0.01-10 0.01-10 Homosalate     0-10  0.01-10 Dimethicone     0-10  0.01-10 0.01-10 Cyclomethicone     0-40  0.01-40  0.01-10 Caprylyl methicone    0-10  0.01-10  0.01-10 Dimethicone crosspolymer     0-90  0.01-90 0.01-90 C30-C45 alkyl cetearyl  0.01-90 dimethicone crosspolymerGlycolic acid     0-10  0.01-10 KCl     0-5  0.01-5  0.01-5  0.01-5Fragrance     0-2     0-2     0-2     0-2 Glutamine/Sodium PCA  0.01-10 0.01-10  0.01-10  0.01-10 Glycine  0.01-10  0.01-10  0.01-10  0.01-10Cystine 0.001-2 0.001-2 0.001-2 0.001-2 Nicotinamide  0.05-10Nicotinamide riboside  0.05-10 Isonicotinamide  0.05-10 N-methylNicotinamide  0.05-10

TABLE III Vanishing Creams VC-1 VC-2 VC-3 VC-4 Water To 100 To 100 To100 To 100 Glycerine     0-5  0.01-5  0.01-5 EDTA  0.01-.01  0.01-.01 0.01-.01  0.01-.01 Preservative  0.02-2  0.02-2  0.02-2  0.02-2 TiO2 0.01-10  0.01-10  0.01-10  0.01-10 Colorant/pigment     0-5  0.01-5 0.01-5 TEA/Sodium Hydroxide/     0-3  0.01-3  0.01-3  0.01-3 potassiumHydroxide Stearic acid     0-30  0.01-30  0.01-30  0.01-30 IsopropylMyristate     0-5  0.01-10  0.01-10 C12-C15 alkyl benzoate     0-5 0.01-10 Brij 35     0-5  0.01-5 Tween40     0-5  0.01-5 Cetyl alcohol    0-2  0.01-2  0.01-2 Ethyl hexyl     0-6  0.01-6  0.01-6methoxycinnamate Butyl     0-3  0.01-3  0.01-3  0.01-3Methoxydibenzoylmethane Ensulizole     0-4  0.01-4 Octisalate     0-5 0.01-5 Octocrylene     0-10  0.01-10  0.01-10 Dimethicone     0-5 0.01-5 Cyclomethicone     0-5  0.01-5 Dimethicone crosspolymer     0-4 0.01-4 Niacinamide     0-5  0.01-5  0.01-5  0.01-5 Hydroxystearic acid    0-5  0.01-5  0.01-5  0.01-5 Fragrance     0-2     0-2     0-2    0-2 Glutamine/Sodium PCA  0.01-10  0.01-10  0.01-10  0.01-10 Glycine 0.01-10  0.01-10  0.01-10  0.01-10 Cystine 0.001-2 0.001-2 0.001-20.001-2 Nicotinamide  0.05-10 Nicotinamide riboside  0.05-10Isonicotinamide  0.05-10 N-methyl Nicotinamide  0.05-10

The invention claimed is:
 1. A topical personal care skin lighteningcomposition comprising: a. skin lightening additive comprising by weightof the composition: i. from about 0.005 to about 1% of cystine; ii. fromabout 0.01 to about 5% of glutamine; iii. from about 0.01 to about 5% ofglycine; and iv. from about 0.1 to about 10% of nicotinamide compound;and b. a cosmetically acceptable carrier in the form of an emulsion; c.wherein the pH of the composition is in the range of from about 3.5 toabout 8.5; wherein the ratio of nicotinamide to total amino acid isabout 20:1 to 50:1.
 2. The composition of claim 1 wherein nicotinamidecompound is nicotinamide riboside.
 3. The composition of claim 1 whereinnicotinamide compound is N-methyl nicotinamide.
 4. The composition ofclaim 1 wherein nicotinamide compound is nicotinamide.
 5. Thecomposition of claim 1 wherein nicotinamide compound is isonicotinamide.6. The composition of claim 1 wherein the composition is in the form ofa water-in-oil emulsion comprising cystine in an aqueous phase, wherein90% of the water droplets have a diameter within the size range of from100 nm to 20 microns.
 7. The composition of claim 1 wherein thecomposition is a leave-on non-solid skin cosmetic composition.
 8. Thecomposition of claim 1 wherein the composition is a vanishing cream. 9.The composition of claim 1 wherein the composition further comprises4-alkyl resorcinol.
 10. The composition of claim 1 wherein thecomposition further comprises 12-hydroxystearic acid.